In previous work, we have determined the mode of attack of activated forms of two carcinogenic aromatic amines on mononucleosides and nucleic acids in vitro. This work, combined with other reported studies, has permitted the testing of a method for predicting the site of reactivity of aromatic electrophiles with purines and pyrimidines. This treatment (developed by G. Klopman to explain the principle of hard and soft acids and bases) includes charge distribution on the reacting molecules, solvation energy, dielectric constant, and mixing of reacting orbitals. Preliminary results (which did not include solvation energy) indicated that the method would be successful with one-electron molecular orbitals (Huckel molecular orbitals), if asked to treat pi-electrons only. Since electrophiles often react at sigma electrons in purines and pyrimidines, a theoretical base with wider capability is obviously necessary. Preliminary studies with iterative extended Huckel theory (IEHT), the least expensive method of performing all-valence-electron calculations, have been encouraging, but the method seems to deal with ions more poorly than the simpler HMO method. Futher studies will consist both of investigating the chemistry of additional activated carcinogens (to test theoretical predictions) and of trying to modify the IEHT calculations in a manner which will yield chemically correct results. Because we are trying to perform calculations for unstable intermediates, it is not possible to check the results with thermochemical data or ionization potentials. Our only check is through actual chemistry, and the fundamental chemical problem consists of predicting the preferred reaction between two multidentate species. Thus, this project has significance for the field of chemical carcinogenesis and for those concerned with the chemistry of aromatic heterocycles.